Lower Gastrointestinal Malignancies

Summary

Lower Gastrointestinal Malignancies

This issue of Radiation Medicine Rounds focuses on lower gastrointestinal malignancies. The American Cancer Society estimates that in 2009 there were a total of 152,000 new cases of colorectal and anal cancers diagnosed with over 50,000 deaths from these cancers. Thus it is crucial for the practitioner to be up-to-date on the latest insights regarding their management.

Included are chapters on the evolution of systemic agents, neoadjuvant treatment, radiation therapy, chemoradiation therapy, rectal cancer and anal cancer covering the vast majority of these tumors. The multi-disciplinary nature of the articles provides readers with an up-to-date summary and a well-rounded review regarding these tumors and their care. Expert authors provide reviews and assessments of the most recent data and its implications for current clinical practice, along with insights into emerging new trends of importance for the near future.

About the Series:

Radiation Medicine Rounds is an invited review publication providing a thorough analysis of new scientific, technologic, and clinical advances in all areas of radiation medicine. There is an emphasis throughout on multidisciplinary approaches to the specialty, as well as on quality and outcomes analysis.

Published three times a year Radiation Medicine Rounds provides authoritative, thorough assessments of a wide range of Ïhot topicsÓ and emerging new data for the entire specialty of radiation medicine.

Features of Radiation Medicine Rounds include:

Editorial board of nationally recognized experts across the spectrum of radiation medicine
In-depth, up-to-date expert reviews and analysis of major new developments in all areas of Radiation Medicine
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Focuses on major topics in Radiation Medicine with in-depth articles covering advances in radiation science radiation medicine technology, radiation medicine practice, and assessment of recent quality and outcomes studies
Emphasizes multidisciplinary approaches to research and practice

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Contents

Foreword

Preface

Contributors

Rectal Cancer

The Evolution of Modern Systemic Agents for Colorectal Cancer

Gregory Heestand, Pamela Kunz, and George A. Fisher

Neoadjuvant Treatment of Rectal Cancer

Christopher G. Willett and Brian G. Czito

Patient Selection for Adjuvant Therapy of Rectal Cancer

Stephen L. Harris and Joel E. Tepper

Intensity-Modulated Radiation Therapy in the Treatment of Rectal Cancer: Current Evidence and Directions for the Future

Foreword

FROM THE EDITOR-IN-CHIEF

Radiation Medicine Rounds is a hardcover periodical published three times a year that is designed to provide an up-to-date review of dedicated radiation medicine topics of interest to clinicians and scientists who are involved in the care of patients receiving radiotherapy. It is intended to serve as both a reference and instructional tool by students, housestaff, fellows, practicing clinicians, medical physicists, cancer biologists, radiobiologists, and interdisciplinary colleagues throughout the oncology spectrum.

For the current issue, Lower Gastrointestinal Malignancies, Guest Editors Drs. Edgar Ben-Josef and Albert Koong have gathered an ensemble of leading-edge thought leaders in the field of gastrointestinal radiation oncology. They are to be congratulated for delivering an educational, research, and clinically applicable product that covers the state-of-the-art for anorectal cancers. On behalf of the editorial board, I congratulate Drs. Ben-Josef and Koong for putting together an outstanding volume that will be useful to colleagues who are involved in the delivery of clinical care to patients requiring radiotherapy for major solid tumors of the lower gastrointestinal tract.

CHARLES R. THOMAS, JR

Preface

The past decade has seen rapid growth in the field of gastrointestinal oncology, encompassing newer insights into gastrointestinal cancer biology and the introduction of many new drugs and advanced technology. This dynamic and rapid evolution is accompanied by controversy and debate. In this issue of Radiation Medicine Rounds we have asked thought leaders in our field to provide the reader with discussions and opinions regarding some of these hot topics.

This issue begins with an article overview on The Evolution of Modern Systemic Agents for Colorectal Cancer. Not only do we, as radiation oncologists, need to keep up with modern new drugs and regimens as they are introduced into practice, but we also need to seize the opportunities for combining them with ionizing radiation. These newer regimens are discussed by Christopher Willett and Brian Czito in Neoadjuvant Treatment of Rectal Cancer.

Since local control is already quite high in rectal cancer, many research questions are starting to revolve around toxicity. The ultimate reduction in radiation toxicity is, of course, through its avoidance. Are there subsets of patients who traditionally were offered adjuvant (or neoadjuvant) chemoradiotherapy but may not need it? This controversial topic of patient selection for adjuvant therapy of rectal cancer will be discussed by Stephen Harris and Joel Tepper. Minimizing toxicity through the use of intensity-modulated radiation therapy (IMRT) is discussed in the next article and minimizing toxicity and improving quality of life through reduction in the scope of surgery or even avoiding it altogether will be discussed in the sixth and seventh articles respectively,

Also included is a discussion on a regimen that is not commonly used in North America but has its merits: short-course versus long-course preoperative radiotherapy. The article, Predictors of Outcome in Rectal Cancer, concludes the material on rectal cancer with a discussion of emerging molecular biomarkers for individualization of therapy. Surely, this is an area of intense interest, as the whole field of oncology is moving in this direction.

The management of anal canal cancer with chemoradiotherapy, and in particular the application of intensity-modulated radiation therapy in this disease, is deliberated by Drs. Goodman, Dasgupta, and Kachnic. This technique holds a lot of promise as it has the potential to reduce skin toxicity, the main cause of morbidity, and treatment interruptions.

The final article, Management of Anal Dysplasia, covers the management of anal dysplasia, a pathology that is encountered with increasing frequency and presents a clinical challenge.

We trust that you will find the content of this book timely, thought provoking, and helpful in your practice.

EDGAR BEN-JOSEF, MD

ALBERT KOONG, MD, PHD

Contributors

Pierre Bohanes, MD

Research Associate

Department of Medical Oncology

USC/Norris Comprehensive Cancer Center

Los Angeles, CA

James D. Brierley, MB, FRCPC

Professor

Department of Radiation Oncology

Princess Margaret Hospital

University of Toronto

Toronto, Ontario, Canada

Daniel T. Chang, MD

Department of Radiation Oncology

Stanford University Medical Center

Stanford, CA

Amanda Clarke, BSC, MBBS, MRCP, FRCR

Department of Radiation Oncology

Mount Vernon Cancer Center

Northwood, Middlesex, UK

Christopher H. Crane, MD

Professor

Department of Radiation Oncology

University of Texas MD Anderson Cancer Center

Houston, TX

Brian G. Czito, MD

Department of Radiation Oncology

Duke University Medical Center

Durham, NC

Prajnan Das, MD, MS, MPH

Assistant Professor

Department of Radiation Oncology

The University of Texas M.D. Anderson Cancer Center

Houston, TX

Tina Dasgupta, MD, PhD

Resident Physician

Department of Radiation Oncology

University of California

San Francisco, CA

George A. Fisher, MD, PhD

Associate Professor

Division of Medical Oncology

Stanford University School of Medicine

Stanford, CA

Joaquim Gama-Rodrigues, MD, PhD

Professor of Surgery

University of São Paulo School of Medicine

Chair

Colorectal Surgery

Angelita and Joaquim Gama Institute

São Paulo, Brazil

Michael C. Garofalo

Assistant Professor

Department of Radiation Oncology

University of Maryland Greenebaum Cancer Center

Baltimore, MD

Karyn A. Goodman, MD, MS

Attending Radiation Oncologist

Department of Radiation Oncology

Memorial Sloan-Kettering Cancer Center

New York, NY

Angelita Habr-Gama, MD, PhD

Professor of Surgery

University of São Paulo School of Medicine

Chair

Colorectal Surgery Division

Angelita and Joaquim Gama Institute

São Paulo, Brazil

Stephen L. Harris, MD

Radiation Oncology

University of North Carolina School of Medicine

Chapel Hill, NC

Gregory Heestand, MD

Clinical Fellow

Division of Medical Oncology

Stanford University School of Medicine

Stanford, CA

Guilherme Pagin São Julião, MD

General Surgery Resident

University of Sao Paulo

São Paulo, Brazil

Lisa A. Kachnic, MD

Chief

Department of Radiation Oncology

Boston Medical Center

Boston, MA

John Kim, MD, FRCPC

Assistant Professor

Department of Radiation Oncology

Princess Margaret Hospital

University of Toronto

Toronto, Ontario, Canada

Pamela Kunz, MD

Assistant Professor

Division of Medical Oncology

Stanford University School of Medicine

Stanford, CA

Percy Lee, MD

Assistant Professor

Department of Radiation Oncology

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, CA

Heinz-Josef Lenz, MD

Professor of Medicine and Preventive Medicine

Department of Medicine and Medical Oncology

USC/Norris Comprehensive Cancer Center

Los Angeles, CA

Niraj Mehta, MD

Resident

Department of Radiation Oncology

UCLA Jonsson Comprehensive Cancer Center

Los Angeles, CA

Rodrigo Oliva Perez, MD, PhD

Colorectal Surgery Division

Department of Gastroenterology

University of São Paulo School of Medicine

Associate

Colorectal Surgery Division

Angelita and Joaquim Gama Institute

São Paulo, Brazil

Carlos Eduardo Pineda, MD

Resident

Department of Surgery

Stanford University School of Medicine

Stanford, CA

Igor Proscurshim, MD

Department of General Surgery

University of São Paulo School of Medicine

Angelita and Joaquim Gama Institute

São Paulo, Brazil

Tracey E. Schefter, MD

Associate Professor Radiation Oncology

Department of Radiation Oncology

University of Colorado Denver

Aurora, CO

Joel E. Tepper, MD

Hector MacLean Distinguished Professor of Cancer Research

Department of Radiation Oncology

UNC/Lineberger Comprehensive Cancer Center

University of North Carolina School of Medicine

Chapel Hill, NC

Christopher G. Willett, MD

L.R. Prosnitz Professor and Chairman

Department of Radiation Oncology

Duke University Health System

Durham, NC

Mark Lane Welton, MD, MHCM, FACS, FASCRS

Professor and Chief, Colon and Rectal Surgery

Department of Surgery

Stanford University School of Medicine

Stanford, CA

The Evolution of Modern Systemic Agents for Colorectal Cancer

Gregory Heestand,* Pamela Kunz, and George A. Fisher?

Stanford University School of Medicine, Stanford, CA

ABSTRACT

Advances in modern chemotherapy have improved the overall survival of patients with colorectal cancer, doubling the median survival of patients with advanced disease. This is largely due to the introduction of new agents—oxaliplatin, irinotecan, and the monoclonal antibodies targeting vascular endothelial growth factor and epidermal growth factor receptor. Better understanding of cell signaling pathways has clarified which patients benefit from specific treatments. Optimization of current dosing regimens and sequencing combinations of the aforementioned agents will likely provide improved quality of life and longevity. The net effect is improved flexibility for oncologists to tailor treatment regimens to specific patient needs.

Cancer of the colon and rectum is the third most common malignancy in the United States, with 146,970 new cases and 49,920 deaths in 2009 (1). According to the Surveillance Epidemiology and End Results database, 39% of newly diagnosed patients present with early stage disease, whereas 36% are diagnosed with regional disease, which carries a higher risk of recurrence following surgery, and 19% present with metastatic disease (2). With advances in chemotherapy, the 5-year disease-free survival following surgery for patients with local and regional disease improved from 51% as reported in 1988 to 73% with the addition of modern adjuvant therapy (3,4). Since 2004, the introduction of targeted therapies has further improved the survival of those with advanced disease. The 5-year survival for all patients with colorectal cancer rose from 50.8% during 1975–1977 to 66.8% during 1999–2005 (2).

This chapter will review the progress that has been made in treating colorectal cancer, from the introduction of fluoropyrimidines to the use of monoclonal antibodies (Table 1).

HISTORICAL PERSPECTIVE: FROM 5-FLUOROURACIL TO MODERN REGIMENS

5-Fluorouracil

The hallmark of colorectal cancer systemic therapy has been 5-fluorouracil (5-FU). 5-FU is a chemical analogue of pyrimidine, the cyclic backbone of the DNA bases thymine and cytosine. 5-FU acts by blocking the production of thymidine monophosphate, thereby inhibiting DNA synthesis (5). 5-FU, either as a series of daily boluses or by continuous infusion, has been used since the 1950s to treat patients with metastatic disease. 5-FU is usually well tolerated, but its common side effects include myelosuppression (more so with bolus than continuous-infusion administration), dermatitis, particularly of the hands and feet, diarrhea, and stomatitis.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) performed a three-armed trial, NSABP C-01, comparing the combination of semustine, vincristine, and 5-FU (MOF) versus Bacillus Calmette-Guérin vaccine versus observation for patients who had undergone surgery for Dukes’ B/C (T2N0 and stage II/III) colon cancer (3). A total of 1,166 patients enrolled, and results reported in 1988 showed that 5-FU-based adjuvant chemotherapy increased the 5-year survival to 67% compared with 59% with surgery alone (P = .05). However, the survival benefit conferred by 5-FU was lost at 10 years, when additional follow-up for C-01 was reported in 2004 (6).

The NSABP also examined the role of adjuvant 5-FU in patients with Dukes’ B/C rectal cancer in the R-01 trial (7). A total of 555 patients who underwent resection of Dukes’ B/C disease were randomized to MOF chemotherapy versus local radiation versus observation. A survival benefit was demonstrated in the chemotherapy arm (P = .05), which was most pronounced in the subset of men with a 5-year survival rate of 60% compared with 37% with surgery alone (P = .001). No survival benefit was shown with radiation alone. A second trial reported by the North Central Cancer Treatment Group (NCCTG) in 1991 compared adjuvant radiation alone with chemotherapy and radiation (8). The chemoradiation arm consisted of 5-FU with semustine before and after radiation, with bolus 5-FU alone during radiation. At 5 years, the chemoradiation arm reported a relative decrease in the rate of cancer recurrence by 34% compared with radiation alone (P = .0025).

Following C-01 and R-01, significant effort was invested in the proper dose and scheduling of 5-FU, as well as the role of presumed synergizing agents including leucovorin (LV) and levamisole. A pooled analysis of earlier adjuvant colon cancer trials by the International Multicentre Pooled Analysis of Colon Cancer Trials group in 1995 demonstrated that adjuvant administration of 5-FU and LV as a daily bolus in a 5-day series every 28 days (later named the Mayo regimen) for six cycles provided a 22% reduction in mortality at 3 years compared with surgery alone in patients with Dukes’ B/C disease (P = .029) (9). However, the daily bolus regimen of 5-FU was associated with significant myelosuppression, mucositis, diarrhea, and nausea.

A combined infusional and bolus regimen of 5-FU (5-FU and LV boluses followed by a 22-hour 5-FU infusion given on days 1 and 2 and repeated every 2 weeks) was found to be superior to bolus 5-FU by de Gramont et al. in 1997. The de Gramont regimen produced significantly less grade III/IV toxicity than bolus 5-FU/LV (11.1% vs 23.9%, P = .0004) and an improved progression-free survival of 27.6 versus 22 weeks (P = .0012) (10). The de Gramont infusion schedule for 5-FU/LV is the basis of later combination regimens (see FOLFOX and FOLFIRI later).

The NCCTG further investigated the timing of 5-FU administration in the adjuvant treatment of rectal cancer (11). Following surgery, 660 patients with stage II/III rectal cancer were randomized to receive concurrent chemoradiation with either bolused or continuous-infusion 5-FU. Patients were also randomized to receive 5-FU versus 5-FU + semustine before and after radiation. Patients receiving continuous-infusion 5-FU chemoradiation had a significantly longer time to relapse compared with the bolused 5-FU chemoradiation patients (P = .01), as well as a superior 4-year survival rate of 70% versus 60%, respectively (P = .005). Semustine did not add benefit to therapy. Thus, continuous-infusion 5-FU with radiation preceded and followed by 5-FU became the standard of care for the adjuvant therapy of rectal cancer.

The main difficulty with infusional 5-FU is that it often requires central venous access to be given with a portable infusion pump. Understandably, many patients are reluctant to have central venous access placed, which can be inconvenient and a nidus for infection. As an alternative to intravenous 5-FU, several oral formulations of 5-FU were developed, including capecitabine. Capecitabine is an orally bioavailable prodrug that is converted to 5-FU by thymidine phosphorylase (12). Capecitabine is traditionally given twice daily and can be given over several days to mimic the serum concentrations of intravenous 5-FU. Similar to infusional 5-FU, common side effects include hand-foot syndrome, rash, diarrhea, and mild myelosuppression.

Capecitabine was approved in 2001 as a single agent for the first-line therapy of metastatic colorectal cancer. This approval was based on two trials totaling 1,207 patients with advanced disease comparing capecitabine dosed at 1,250 mg/m² by mouth twice daily for 14 days every 3 weeks compared with bolus 5-FU/LV (13,14). These trials reported the median time to disease progression with capecitabine to be 4.3 and 5.2 months, compared with 4.7 months for bolus 5-FU/LV. The differences were not statistically significant, and capecitabine’s approval was based on equivalence rather than superiority to bolus 5-FU/LV. Hoff et al. (14) demonstrated an improved overall response rate of 24.8% with capecitabine compared with 15.5% with bolus 5-FU/LV (P = .005).

Capecitabine can also be used as a single agent for adjuvant therapy for patients with colon cancer. This indication is based on the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial, which randomized 1,987 patients with stage III disease to receive capecitabine versus bolus 5-FU/LV following surgery (15). With a hazard ratio of 0.87 for disease-free survival, capecitabine was equivalent to bolus 5-FU/LV, but with significantly less toxicity (P < .001).

The role of adjuvant capecitabine combined with radiation for patients with rectal cancer is less clear. Capecitabine is a reasonable substitute for continuous-infusion 5-FU during radiation and is frequently used in this setting. The NSABP R-04 trial is the first randomized trial to address the role of capecitabine versus 5-FU in the preoperative therapy of rectal cancer (16). In this trial, patients are randomized to receive either capecitabine ± oxaliplatin (discussed later) or continuous-infusion 5-FU ± oxaliplatin during radiation. The primary endpoint is local recurrence rate.

Irinotecan

Significant improvement in systemic therapy for colorectal cancer occurred in the 1990s with the introduction of new cytotoxic agents. The first to arrive was irinotecan, which is a derivative of the naturally occurring compound camptothecin. Irinotecan is administered intravenously and hydrolyzed in patient serum to form a cytotoxic complex with topoisomerase I, thereby causing irreparable DNA damage during replication. Irinotecan is generally well tolerated, but side effects can include diarrhea and myelosuppression.

Irinotecan was introduced in 1996 using a dose of 125 mg/m² intravenously over 90 minutes for patients with metastatic colorectal cancer refractory to 5-FU, given weekly for 4 weeks, followed by 2 weeks off. Pooled analysis of three single-arm phase II trials demonstrated that this regimen provided a median survival of 5.8 months (17–20). An alternative dosing regimen administering irinotecan once every 3 weeks at 300 to 350 mg/m² resulted in a median survival of 9.2 months compared with 6.2 months with best supportive care in a randomized trial (n = 279, P = .0001) (21).

The obvious question remaining was whether there is a role for irinotecan in adjuvant therapy for colorectal cancer. This question was first addressed by the Pan-European Trials in Alimentary Tract Cancers (PETACC-3) trial in Europe, which randomized 2,094 patients with stage III colon cancer to receive 12 cycles of FOLFIRI versus infusional 5-FU/LV following surgery (26). The 5-year survival of both arms was equivalent at 73.6% versus 71.3%, respectively (P = .094). The Cancer and Leukemia Group B performed a similar trial in the United States comparing IFL and weekly bolus 5-FU/LV as adjuvant therapy and also reported no benefit with the addition of irinotecan (27). To date, there has been no benefit with irinotecan added to 5-FU chemoradiation in the adjuvant or neoadjuvant settings for patients with rectal cancer (28).

Oxaliplatin

The second significant new cytotoxic agent in the treatment of colorectal cancer to emerge during the 1990s was oxaliplatin. Oxaliplatin is a third-generation platinum compound and was developed to minimize the severe nausea and renal toxicity associated with cisplatin use. A phase I trial performed in France reported that oxaliplatin was associated with a cumulative peripheral sensory neuropathy, often exacerbated by contact with cold, as well as grade III nausea (29).

The first randomized trial with oxaliplatin randomized 420 patients with metastatic colorectal cancer to receive FOLFOX4 (oxaliplatin 85/m² on day 1 + de Gramont infusional 5-FU/LV) versus infusional 5-FU/LV alone (30). The use of FOLFOX4 significantly improved the median progression-free survival to 9.0 months compared with 6.2 months with 5-FU/LV (P = .0003). However, there was only a trend toward a survival advantage at 16.2 months with FOLFOX4 compared with 14.7 months with 5-FU/LV (P = .12).

A North American intergroup trial was more compelling. A total of 795 patients with untreated metastatic colorectal cancer were randomized to three arms: FOLFOX4 versus IFL versus a combined regimen of irinotecan and oxaliplatin (IROX) (31). The median overall survival for FOLFOX4 was 19.5 months compared with 15.0 months for IFL (P = .0001) and 17.4 months for IROX (P = .04). The combination of oxaliplatin with irinotecan proved to be more toxic than FOLFOX4, with increased grade III/IV emesis (22% vs. 3%, P = .001) and diarrhea (24% vs. 12%, P = .001), although FOLFOX4 had more paresthesias (18% vs. 7%, P = .001). FOLFOX4 also had significantly less gastrointestinal toxicity compared with IFL.

With the activity of oxaliplatin established in advanced disease, its role in the adjuvant setting was investigated in France with the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial. The MOSAIC trial, which randomized 2,246 patients with stage II and III colon cancer to FOLFOX4 versus infusional 5-FU/LV for 12 cycles, demonstrated a 3-year disease-free survival of 78.2% versus 72.9% favoring FOLFOX4 (P = .002) (32). Follow-up of the MOSAIC trial was published in 2009 (4). Five-year disease-free survival continued to favor FOLFOX4 at 73.3% versus 67.4% (P = .003), with a 6-year overall survival of 78.5% versus 76.0%, respectively (P = .046). Subgroup analysis revealed that most of the adjuvant benefit of FOLFOX4 was conferred to patients with stage III disease. FOLFOX4 did not convey a statistically significant improvement in 6-year overall survival in patients with stage II disease—86.9% versus 86.8% for 5-FU/LV (P = .986). However, in patients with stage III disease, the 6-year overall survival for patients receiving FOLFOX4 was 72.9% versus 68.7% (P = .023). A more recent analysis of these data indicated that the benefit in stage III patients occurred predominantly in patients younger than 70 years (33). The role of adjuvant therapy in stage II disease